Abstract
Purpose
Loss of coxsackievirus and adenovirus receptor (CAR) is frequently observed in malignant cancer, hampering adenoviral gene therapy approaches. Complexing adenovirus with cationic liposomes can increase adenoviral transgene expression, particularly in cells with CAR-deficiency. We investigated whether other factors such as lipid composition might be involved in determining the efficiency of liposome-complexed adenoviral gene transfer in cancer cells.
Material and methods
Human cancer cell lines with different expression levels of CAR were infected with a GFP transgene. The efficiency of transgene expression was assessed by determining GFP expression using FACS analysis.
Results
The efficiency of liposome-complexed adenoviral gene transfer was dependent on the lipid composition constituting liposomes. Polyethylene glycol (PEG)-containing liposomes were most effective in increasing liposome-complexed adenoviral gene transfer. In CAR-deficient cells, use of PEG-containing liposomes enhanced adenoviral gene transfer, whereas in CAR-expressing cells enhancement varied depending on cell type. In some CAR-expressing cells, the effect of liposome complexing was even comparable to that in CAR-deficient cells. Increased adenoviral transgene expression following complexing with PEG-containing liposomes correlated with liposome uptake in cancer cells.
Conclusions
Liposome-complexed adenoviral gene transfer appears to depend on lipid composition and the level of liposome uptake by cancer cells, in addition to CAR levels. Our study suggest that these multiple factors should be considered in designing liposome-complexed adenoviral vectors to improve outcomes of current adenoviral cancer gene therapies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anders M, Christian C, Mcmahon M, et al (2003) Inhibition of the Rsf/MEK/ERK pathway up-regulates expression of the Coxsackievirus and Adenovirus receptor in cancer cells. Cancer Res 63:2088–2095
Asaoka K, Tada M, Sawamura Y, Ikeda J, Abe H (2000) Dependence of efficient gene delivery in malignant glioma cells on the expression levels of the Coxsackievirus and adenovirus receptor. J Neurosurg 92:1002–1008
Bergelson JM, Cunningham JA, Droguett G, et al (1997) Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275:1320–1323
Bruning A, Ronnebaum IB (2003) CAR is a cell-cell adhesion protein in human cancer cells and is expressionally modulated by dexamethasone, TNFα, and TGFβ. Gene Ther 9:619–624
Buttgereit P, Weineck S, Ropke G, Marten A, Brand K, Heinicke T, Caselmann WH, Huhn D, Schmidt-Wolf IGH (2000) Efficient gene transfer into lymphoma cells using adenoviral vectors combined with lipofection. Cancer Gene Ther 7:1145–1155
Byk T, Haddada H, Vainchenker W, Louache F (1998) Lipofectamine and related cationic lipids strongly improve adenoviral infection efficiency of primitive human hematopoietic cells. Human Gene Ther 9:2493–2502
Carlisle RC (2002) Use of adenovirus proteins to enhance the transfection activity of synthetic gene delivery systems. Curr Opin Mol Ther 4:306–312
Chillon M, Lee JH, Fasbender A, et al (1998) Adenovirus complexed with polyethylene glycol and cationic lipid is shielded from neutralizing antibodies in vitro. Gene Ther 5:995–1002
Fasbender AI, Zabner J, Chillon M, Moninger TO, Puga AP, Davidson BL, Welsh MJ (1997) Complexes of adenovirus with polycationic polymers and cationic lipids increase the efficiency of gene transfer in vitro and in vivo. J Biol Chem 272:6479–6489
Fenske DB, Palmer LR, Chen T, et al (2001) Cationic poly(ethylenelycol) lipids incorporated into pre-formed vesicles enhance binding and uptake to BHK cells. Biochim Biophys Acta 1512:259–272
Hemminki A, Kanerva A, Liu B, Wang M, Alvarez RD, Siegal GP, Curiel DT (2003) Modulation of coxsackie-adenovirus receptor expression for increased adenoviral transgene expression. Cancer Res 63:847–853
Jee YS, Lee SG, Lee JC, et al (2002) Reduced expression of coxsackievirus and adenovirus receptor (CAR) in tumor tissue compared to normal epithelium in head and neck squamous cell carcinoma patients. Anticancer Res 22:2629–2634
Kim M, Zinn KR, Barnett BG, et al (2002) The therapeutic efficacy of adenoviral vectors for cancer gene therapy is limited by a low level of primary adenovirus receptors on tumor cells. Eur J Cancer 38:1917–1926
Kitazono M, Goldsmith ME, Aikou T, Bates S, Fojo T (2001) Enhanced adenovirus transgene expression in malignant cells treated with the histone deacetylase inhibitor FR901228. Cancer Res 61:6328–6330
Lee SG, Yoon SJ, Kim CD, Kim K, Lim DS, Yeom YI, Sung MW, Heo DS, Kim NK (2000) Enhancement of adenoviral transducton with polycationic liposomes in vivo. Cancer Gene Ther 7:1329–1335
Li Y, Pong RC, Bergelson JM, et al (1999) Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. Cancer Res 59:325–330
Maizel J, White D, Scharff M (1968) The polypeptides of adenovirus. I. evidence for multiple protein components in the virion and a comparison of types 2, 7A, and 12. Virol 36:115–125
Maurer N, Mori A, Palmer L, et al (1999) Lipid-based systems for the intracellular delivery of genetic drugs. Mol Membr Biol 16:129–140
Mok KW, Lam AM, Cullis PR (1999) Stabilized plasmid-lipid particles: factors influencing plasmid entrapment and transfection properties. Biochim Biophys Acta 1419:137–150
Okegawa T, Li Y, Pong RC, Bergelson JM, Zhou J, Hsieh JT (2000) The dual impact of Coxsackie and adenovirus receptor expression on human prostate cancer gene therapy. Cancer Res 60:5031–5036
Pouton CW, Seymour LW (2001) Key issues in non-viral gene delivery. Adv Drug Deliv Rev 46:187–203
Qiu C, De Young MB, Finn A, et al (1998) Cationic liposomes enhance adenovirus entry via a pathway independent of the fiber receptor and alpha(v)-integrins. Hum Gene Ther 9:507–520
Ross PC, Hui SW (1999) Polyehylene glycol enhances lipoplex-cell association and lipofection.Biochim Biophys Acta 1421:273–283
Song LY, Ahkong QF, Rong Q, Wang S, Ansell MJ, Mui HB (2002) Characterization of the inhibitory effect of PEG-lipid conjugates on the intracellular delivery of plasmid and antisense DNA mediated by cationic lipid liposomes. Biochim Biophys Acta 1558:1–13
Toyoda K, Nakane H, Heistad DD (2001) Cationic polymer and lipids augment adenovirus-mediated gene transfer to cerebral arteries in vivo. J Cerebral Blood Flow Metabolism 21:1225–1131
Uchida E, Mizuguchi H, Ishii-Watabe A, Hayakawa T (2002) Comparison of the efficiency and safety of nonviral vector-mediated gene transfer into a wide range of cancer cells. Biol Pharm Bull 25:891–897
Wickham TJ, Mathias P, Cheresh DA, et al (1993) Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell 3:309–319
Yoshimura K, Rosenfeld M, Seth P, et al (1993) Adenovirus-mediated augmentation of cell transfection with unmodified plasmid vectors. J Biol Chem 268:2300–2303
Yotnda P, Chen DH, Chiu W, Piedra PA, Davis A, Templeton NS, Brenner MK (2002) Bilamellar cationic liposomes protect adenovirus from preexisting humoral immune responses. Mol Ther 5:233–241
Acknowledgement
This work was supported by a research grant from the National Cancer Center
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lee, E.M., Hong, S.H., Lee, Y.J. et al. Liposome-complexed adenoviral gene transfer in cancer cells expressing various levels of coxsackievirus and adenovirus receptor. J Cancer Res Clin Oncol 130, 169–177 (2004). https://doi.org/10.1007/s00432-003-0521-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-003-0521-z